Cascone Tina, Morelli Maria Pia, Morgillo Floriana, Kim Woo-Young, Rodolico Gabriella, Pepe Stefano, Tortora Giampaolo, Berrino Liberato, Lee Ho-Young, Heymach John V, Ciardiello Fortunato
Division of Medical Oncology, Department of Clinical and Experimental Medicine and Surgery F. Magrassi and A. Lanzara, Second University of Naples, Naples, Italy.
J Cell Physiol. 2008 Sep;216(3):698-707. doi: 10.1002/jcp.21444.
The proteasome plays a pivotal role in the turnover of regulatory transduction proteins induced by activated cell membrane growth factor receptors. The epidermal growth factor receptor (EGFR) pathway is crucial in the development and progression of human epithelial cancers. Proteasome inhibition may sensitize human cancer cell lines to EGFR inhibitors. We investigated the growth inhibitory and pro-apoptotic effects of the proteasome inhibitor bortezomib in combination with anti-EGFR drugs, such as gefitinib, vandetanib, and cetuximab in EGFR-expressing human cancer cell lines. Bortezomib determined dose-dependent growth inhibition in a nine cancer cell line panel (IC(50) values, range 6-42 nM). A significant synergistic growth inhibitory effect was observed with the combination of bortezomib and each EGFR inhibitor in all cell lines (combination index, CI, range 0.10-0.55), which was accompanied by a significant induction in apoptosis by the combined treatment with bortezomib, cetuximab and vandetanib. In HCT-116 colon cancer and A549 lung adenocarcinoma cells, bortezomib plus EGFR inhibitor treatment induced a more effective inhibition of EGFR-activated down-stream signals, including a marked suppression in activated, phosphorylated Akt (P-Akt). In contrast, overexpression of a constitutively active P-Akt protected A549 cells by cell growth inhibition and apoptosis following treatment with bortezomib and EGFR inhibitors. The combined treatment with bortezomib and EGFR inhibitors has a synergistic growth inhibitory and pro-apoptotic activity in different human cancer cells which possess a functional EGFR-dependent autocrine growth pathway through to a more efficient and sustained inhibition of Akt.
蛋白酶体在由活化的细胞膜生长因子受体诱导的调节转导蛋白的周转中起关键作用。表皮生长因子受体（EGFR）通路在人类上皮癌的发生和发展中至关重要。蛋白酶体抑制可能使人类癌细胞系对EGFR抑制剂敏感。我们研究了蛋白酶体抑制剂硼替佐米与抗EGFR药物（如吉非替尼、凡德他尼和西妥昔单抗）联合使用对表达EGFR的人类癌细胞系的生长抑制和促凋亡作用。硼替佐米在9种癌细胞系中呈现剂量依赖性生长抑制（IC(50)值范围为6 - 42 nM）。在所有细胞系中，硼替佐米与每种EGFR抑制剂联合使用均观察到显著的协同生长抑制作用（联合指数，CI，范围为0.10 - 0.55），同时硼替佐米、西妥昔单抗和凡德他尼联合治疗显著诱导了细胞凋亡。在HCT - 116结肠癌细胞和A549肺腺癌细胞中，硼替佐米加EGFR抑制剂治疗能更有效地抑制EGFR激活的下游信号，包括显著抑制活化的磷酸化Akt（P - Akt）。相反，组成型活性P - Akt的过表达通过硼替佐米和EGFR抑制剂处理后抑制细胞生长和诱导凋亡来保护A549细胞。硼替佐米与EGFR抑制剂联合治疗在不同的人类癌细胞中具有协同生长抑制和促凋亡活性，这些癌细胞拥有功能性EGFR依赖的自分泌生长途径，可更有效且持续地抑制Akt。
